Extrafollicular IgD-CD27-CXCR5-CD11c- DN3 B cells infiltrate inflamed tissues in autoimmune fibrosis and in severe COVID-19.

Although therapeutic B cell depletion dramatically resolves inflammation in many diseases in which antibodies appear not to play a central role, distinct extrafollicular pathogenic B cell subsets that accumulate in disease lesions have hitherto not been identified. The circulating immunoglobulin D (IgD)-CD27-CXCR5-CD11c+ DN2 B cell subset has been previously studied in some autoimmune diseases. A distinct IgD-CD27-CXCR5-CD11c- DN3 B cell subset accumulates in the blood both in IgG4-related disease, an autoimmune disease in which inflammation and fibrosis can be reversed by B cell depletion, and in severe COVID-19. These DN3 B cells prominently accumulate in the end organs of IgG4-related disease and in lung lesions in COVID-19, and double-negative B cells prominently cluster with CD4+ T cells in these lesions. Extrafollicular DN3 B cells may participate in tissue inflammation and fibrosis in autoimmune fibrotic diseases, as well as in COVID-19.

Outcomes during and after long-term tocilizumab treatment in patients with giant cell arteritis.

OBJECTIVE: To assess outcomes in giant cell arteritis (GCA) patients during and after long-term tocilizumab (TCZ) treatment. METHODS: Retrospective analysis of GCA patients treated with TCZ at a single centre (2010-2022). Time to relapse and annualised relapse rate during and after TCZ treatment, prednisone use, and safety were assessed. Relapse was defined as reappearance of any GCA clinical manifestation that required treatment intensification, regardless of C reactive protein levels and erythrocyte sedimentation rate. RESULTS: Sixty-five GCA patients were followed for a mean (SD) of 3.1 (1.6) years. The mean duration of the initial TCZ course was 1.9 (1.1) years. The Kaplan-Meier (KM)-estimated relapse rate at 18 months on TCZ was 15.5%. The first TCZ course was discontinued due to satisfactory remission achievement in 45 (69.2%) patients and adverse events in 6 (9.2%) patients. KM-estimated relapse rate at 18 months after TCZ discontinuation was 47.3%. Compared with patients stopping TCZ at or before 12 months of treatment, the multivariable adjusted HR (95% CI) for relapse in patients on TCZ beyond 12 months was 0.01 (0.00 to 0.28; p=0.005). Thirteen patients received >1 TCZ course. Multivariable adjusted annualised relapse rates (95% CI) in all periods on and off TCZ aggregated were 0.1 (0.1 to 0.2) and 0.4 (0.3 to 0.7), respectively (p=0.0004). Prednisone was discontinued in 76.9% of patients. During the study, 13 serious adverse events occurred in 11 (16.9%) patients. CONCLUSION: Long-term TCZ treatment was associated with remission maintenance in most patients with GCA. The estimated relapse rate by 18 months after TCZ discontinuation was 47.3%.

#COVIDisAirborne: AI-enabled multiscale computational microscopy of delta SARS-CoV-2 in a respiratory aerosol.

We seek to completely revise current models of airborne transmission of respiratory viruses by providing never-before-seen atomic-level views of the SARS-CoV-2 virus within a respiratory aerosol. Our work dramatically extends the capabilities of multiscale computational microscopy to address the significant gaps that exist in current experimental methods, which are limited in their ability to interrogate aerosols at the atomic/molecular level and thus obscure our understanding of airborne transmission. We demonstrate how our integrated data-driven platform provides a new way of exploring the composition, structure, and dynamics of aerosols and aerosolized viruses, while driving simulation method development along several important axes. We present a series of initial scientific discoveries for the SARS-CoV-2 Delta variant, noting that the full scientific impact of this work has yet to be realized.

#COVIDisAirborne: AI-enabled multiscale computational microscopy of delta SARS-CoV-2 in a respiratory aerosol

We seek to completely revise current models of airborne transmission of respiratory viruses by providing never-before-seen atomic-level views of the SARS-CoV-2 virus within a respiratory aerosol. Our work dramatically extends the capabilities of multiscale computational microscopy to address the significant gaps that exist in current experimental methods, which are limited in their ability to interrogate aerosols at the atomic/molecular level and thus obscure our understanding of airborne transmission. We demonstrate how our integrated data-driven platform provides a new way of exploring the composition, structure, and dynamics of aerosols and aerosolized viruses, while driving simulation method development along several important axes. We present a series of initial scientific discoveries for the SARS-CoV-2 Delta variant, noting that the full scientific impact of this work has yet to be realized.

Intelligent resolution: Integrating Cryo-EM with AI-driven multi-resolution simulations to observe the severe acute respiratory syndrome coronavirus-2 replication-transcription machinery in action

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) replication transcription complex (RTC) is a multi-domain protein responsible for replicating and transcribing the viral mRNA inside a human cell. Attacking RTC function with pharmaceutical compounds is a pathway to treating COVID-19. Conventional tools, e.g. cryo-electron microscopy and all-atom molecular dynamics (AAMD), do not provide sufficiently high resolution or timescale to capture important dynamics of this molecular machine. Consequently, we develop an innovative workflow that bridges the gap between these resolutions, using mesoscale fluctuating finite element analysis (FFEA) continuum simulations and a hierarchy of AI-methods that continually learn and infer features for maintaining consistency between AAMD and FFEA simulations. We leverage a multi-site distributed workflow manager to orchestrate AI, FFEA, and AAMD jobs, providing optimal resource utilization across HPC centers. Our study provides unprecedented access to study the SARS-CoV-2 RTC machinery, while providing general capability for AI-enabled multi-resolution simulations at scale.

Expert Perspective: Management of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) comprise a major subset of diseases that cause destructive inflammation of small and medium-sized blood vessels. Although these conditions have a predilection for pulmonary and renal involvement, they are in fact protean diseases that can involve essentially any organ system. AAV is among the most difficult rheumatic diseases to diagnose and treat. Therapy for AAV has evolved over the past two decades. Rituximab, an anti-CD20 monoclonal antibody, is now the preferred agent for remission induction in conjunction with a reduced-dose glucocorticoid taper. Rituximab is also often a key therapy for remission maintenance. Glucocorticoid toxicity reduction has become a major priority for treatment regimens. Avacopan, an important new adjunct to remission induction therapy, may reduce glucocorticoid use and its resulting toxicity. The role of avacopan as a remission maintenance agent requires further study. The duration of immunosuppression following remission is guided by a number of factors, including the patient's overall clinical state, the degree of damage from previous disease activity, the tolerability of remission maintenance medications, and SARS-CoV-2 vaccination and immunity status. Certain features, including history of previous relapse, the presence of ANCA directed against proteinase 3, and a diagnosis of granulomatosis with polyangiitis, favor prolonged remission maintenance therapy. The interval between rituximab doses can usually be lengthened over time during the maintenance phase.

Interleukin-6 inhibitors reduce mortality in coronavirus disease-2019: An individual patient data meta-analysis from randomized controlled trials.

OBJECTIVE: To assess the efficacy of IL-6 inhibitors compared to standard of care (SOC) in COVID-19 patients. DATA SOURCES: A systematic review of the MEDLINE and Scopus databases (last search: October 8th, 2021) was performed according to the PRISMA statement. STUDY SELECTION: Randomized control trials (RCTs) comparing IL-6 inhibitors to SOC in hospitalized COVID-19 patients were deemed eligible. DATA EXTRACTION AND SYNTHESIS: Individual patient data were extracted from the Kaplan-Meier curves or were obtained from authors of included studies. Additionally, the reviewers independently abstracted data and assessed study quality of each eligible report. RESULTS: Eleven studies were identified, incorporating 7467 patients (IL-6 inhibitors: 4103, SOC: 3364). IL-6 inhibitors were associated with decreased risk for death compared to SOC at the one-stage meta-analysis (Hazard Ratio [HR]: 0.75, 95% Confidence interval [CI]: 0.69-0.82, p<0.0001) and the two-stage meta-analysis (HR: 0.85, 95%CI: 0.77-0.93, p<0.001, I2 = 0.0%). Meta-regression analysis revealed that the difference in OS between the two groups was not influenced by the mean age of patients. At secondary meta-analyses, IL-6 inhibitors were associated with decreased odds for intubation OR:0.74, 95%CI:0.65-0.85, p<0.001, I2=0.0%). IL-6 inhibitors were associated with increased odds for discharge compared to SOC (OR:1.28, 95% CI:1.15-1.42, p<0.001, I2=0.0%). CONCLUSIONS AND RELEVANCE: This meta-analysis of individual patient data from randomized trials shows that IL-6 inhibitors significantly reduce the risk of death compared to SOC. IL-6 inhibitors are also associated with better outcomes in terms of intubation and discharge rates compared to SOC.

Lessons Learned from Responsive Molecular Dynamics Studies of the COVID-19 Virus.

Over the past 18 months, the need to perform atomic detail molecular dynamics simulations of the SARS-CoV-2 virion, its spike protein, and other structures related to the viral infection cycle has led biomedical researchers worldwide to urgently seek out all available biomolecular structure information, appropriate molecular modeling and simulation software, and the necessary computing resources to conduct their work. We describe our experiences from several COVID-19 research collaborations and the challenges they presented in terms of our molecular modeling software development and support efforts, our laboratory's local computing environment, and our scientists' use of non-traditional HPC hardware platforms such as public clouds for large scale parallel molecular dynamics simulations.

Evaluation of the toxicity of glucocorticoids in patients with autoimmune blistering disease using the Glucocorticoid Toxicity Index: A cohort study.

BACKGROUND: Glucocorticoids are the mainstay of treatment for autoimmune blistering diseases (AIBDs). The Glucocorticoid Toxicity Index (GTI) is a novel, outcome-based glucocorticoid-induced adverse effects monitoring instrument. OBJECTIVE: To investigate whether the GTI score was able to accurately quantify the glucocorticoid-induced toxicity in patients with AIBDs. METHODS: The prospective cohort study included patients with confirmed diagnoses of AIBDs (group1, currently receiving glucocorticoids; and group 2, had glucocorticoids ceased earlier). Data were collected minimally at baseline (V1) and 3 months (V2). Further data from patients who were able to complete the follow-up visits at 6 months (V3) and 12 months (V4) amid the COVID-19 pandemic were also included. GTI scores were calculated after data collection. RESULTS: Analysis of data from V1 and V2 found a linear correlation between GTI score and prednisone doses (P < .05) and a significant difference in GTI scores between group1 and group 2 (P < .05). Data from V3 and V4 suggested that GTI scores continued to rise progressively alongside increasing cumulative prednisone dose. LIMITATIONS: Small sample size, further exacerbated by the COVID-19 pandemic. Single-center study. CONCLUSION: The GTI sensitively and specifically captured the changes in glucocorticoids toxicity over time among patients with AIBDs. The GTI could be a feasible tool that can be used in future clinical trials as a glucocorticoid-induced toxicity outcome measure.

Perceived Risk and Associated Shielding Behaviors in Patients With Rheumatoid Arthritis During the Coronavirus 2019 Pandemic.

OBJECTIVE: To investigate the perceived risk of coronavirus disease 2019 (COVID-19) infection and outcomes as well as shielding practices among patients with rheumatoid arthritis (RA) during the COVID-19 pandemic. METHODS: We surveyed participants with RA in a large health care system between July 16 and November 8, 2020. Participants reported RA treatment, COVID-19 risk perception, and shielding practices (eg, masks, social distancing, and quarantining). We examined the association of demographic and disease-specific factors with risk perception and the association of risk perception with shielding practices. RESULTS: Of 494 participants, 195 (40%), 169 (34%), and 130 (26%) strongly agreed, agreed, or were uncertain/disagreed that their RA put them at higher risk for COVID-19 or poor outcomes, respectively. Younger age (odds ratio [OR]: 0.98), having a comorbidity (OR: 1.60), and biologic disease-modifying antirheumatic drug (bDMARD) use (OR: 1.75) were independently associated with a higher perceived risk. Among those who strongly agreed, agreed, or were uncertain/disagreed that they had greater risk, 165 (85%), 118 (70%), and 69 (53%), respectively, practiced all three shielding measures (P < 0.0001). Those who strongly agreed or agreed that they were at higher risk were more likely to use all three shielding practices (OR: 4.16 and 1.97, respectively). bDMARD use and glucocorticoid use were associated with using all three shielding measures (OR: 1.99 and 1.81, respectively). CONCLUSION: Perception of COVID-19 risk among patients with RA varies substantially. Factors associated with perceived risk are different from those found to be associated with worse outcomes in observational studies. Greater perceived risk is associated with more strict shielding, which has implications for patient education and mental health.

Immunomodulation as Treatment for Severe Coronavirus Disease 2019: A Systematic Review of Current Modalities and Future Directions.

In severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, viral load peaks early and declines quickly after symptom onset. Severe coronavirus disease 2019 (COVID-19) is marked by aberrant innate and adaptive immune responses with an abnormal cytokine profile and multiorgan system dysfunction that persists well after viral clearance. A purely antiviral treatment strategy may therefore be insufficient, and antiviral agents have not shown a benefit later in the illness course. A number of immunomodulatory strategies are being tested, including corticosteroids, cytokine and anticytokine therapies, small molecule inhibitors, and cellular therapeutics. To date, the only drug to show a mortality benefit for COVID-19 in a randomized, controlled trial is dexamethasone. However, there remains uncertainty about which patients may benefit most and about longer-term complications, including secondary infections. Here, we review the immune dysregulation of severe COVID-19 and the existing data behind various immunomodulatory strategies, and we consider future directions of study.

AI-driven multiscale simulations illuminate mechanisms of SARS-CoV-2 spike dynamics

We develop a generalizable AI-driven workflow that leverages heterogeneous HPC resources to explore the time-dependent dynamics of molecular systems. We use this workflow to investigate the mechanisms of infectivity of the SARS-CoV-2 spike protein, the main viral infection machinery. Our workflow enables more efficient investigation of spike dynamics in a variety of complex environments, including within a complete SARS-CoV-2 viral envelope simulation, which contains 305 million atoms and shows strong scaling on ORNL Summit using NAMD. We present several novel scientific discoveries, including the elucidation of the spike?s full glycan shield, the role of spike glycans in modulating the infectivity of the virus, and the characterization of the flexible interactions between the spike and the human ACE2 receptor. We also demonstrate how AI can accelerate conformational sampling across different systems and pave the way for the future application of such methods to additional studies in SARS-CoV-2 and other molecular systems.

Scalable Analysis of Authentic Viral Envelopes on FRONTERA.

Enveloped viruses, such as SARS-CoV-2, infect cells via fusion of their envelope with the host membrane. By employing molecular simulations to characterize viral envelopes, researchers can gain insights into key determinants of infection. Here, the Frontera supercomputer is leveraged for large-scale modeling and analysis of authentic viral envelopes, whose lipid compositions are complex and realistic. Visual Molecular Dynamics (VMD) with support for MPI is employed, overcoming previous computational limitations and enabling investigation into virus biology at an unprecedented scale. The techniques applied here to an authentic HIV-1 envelope at two levels of spatial resolution (29 million particles and 280 million atoms) are broadly applicable to the study of other viruses. The authors are actively employing these techniques to develop and characterize an authentic SARS-CoV-2 envelope. A general framework for carrying out scalable analysis of simulation trajectories on Frontera is presented, expanding the utility of the machine in humanity's ongoing fight against infectious diseases.

Efficacy of Tocilizumab in Patients Hospitalized with Covid-19.

BACKGROUND: The efficacy of interleukin-6 receptor blockade in hospitalized patients with coronavirus disease 2019 (Covid-19) who are not receiving mechanical ventilation is unclear. METHODS: We performed a randomized, double-blind, placebo-controlled trial involving patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, hyperinflammatory states, and at least two of the following signs: fever (body temperature >38°C), pulmonary infiltrates, or the need for supplemental oxygen in order to maintain an oxygen saturation greater than 92%. Patients were randomly assigned in a 2:1 ratio to receive standard care plus a single dose of either tocilizumab (8 mg per kilogram of body weight) or placebo. The primary outcome was intubation or death, assessed in a time-to-event analysis. The secondary efficacy outcomes were clinical worsening and discontinuation of supplemental oxygen among patients who had been receiving it at baseline, both assessed in time-to-event analyses. RESULTS: We enrolled 243 patients; 141 (58%) were men, and 102 (42%) were women. The median age was 59.8 years (range, 21.7 to 85.4), and 45% of the patients were Hispanic or Latino. The hazard ratio for intubation or death in the tocilizumab group as compared with the placebo group was 0.83 (95% confidence interval [CI], 0.38 to 1.81; P = 0.64), and the hazard ratio for disease worsening was 1.11 (95% CI, 0.59 to 2.10; P = 0.73). At 14 days, 18.0% of the patients in the tocilizumab group and 14.9% of the patients in the placebo group had had worsening of disease. The median time to discontinuation of supplemental oxygen was 5.0 days (95% CI, 3.8 to 7.6) in the tocilizumab group and 4.9 days (95% CI, 3.8 to 7.8) in the placebo group (P = 0.69). At 14 days, 24.6% of the patients in the tocilizumab group and 21.2% of the patients in the placebo group were still receiving supplemental oxygen. Patients who received tocilizumab had fewer serious infections than patients who received placebo. CONCLUSIONS: Tocilizumab was not effective for preventing intubation or death in moderately ill hospitalized patients with Covid-19. Some benefit or harm cannot be ruled out, however, because the confidence intervals for efficacy comparisons were wide. (Funded by Genentech; ClinicalTrials.gov number, NCT04356937.).